CS241062B2 - Method of anti-inflammation agent production for local application - Google Patents

Abstract

A novel formulation of piroxicam for dermatological administration is disclosed. Pharmaceutical compositions containing proxicam, lower alkanols, water, carboxyvinyl polymer, polyhydric alcohols, alkanolamines and optionally film-forming agents are prepared, said compositions having a pH of from about 6.5 to about 9.0. The novel formulation is characterized by excellent applicability on the skin, skin-permeability and good stability. The novel formulation, which is in gel ointment form, is as effective as orally administered piroxicam and is well suited for topical administration through skin for the treatment of various types of inflammatory conditions.

Description

The invention relates to a method. for the preparation of an anti-inflammatory agent for topical administration containing piroxicam, i.e. N- [2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid as active ingredient. 1-Dioxide of the formula 1-dioxide

The process according to the invention makes it possible to obtain a suitable one. a topical formulation comprising an anti-inflammatory amount of the active ingredient, a nontoxic base, and appropriate solvents.

Piroxicam is a non-steroidal anti-inflammatory agent that has been described under its chemical name by J. G. Lomlardin in U.S. Patent No. 3,541,584 and which is highly effective in mammals when administered against chronic. . joint inflammation, arthritis, arthritis deformans, cross and shoulder pain, cervico-omo-brachial syndrome, trauma 241062, or pain caused by tooth extraction. Piroxicam is throughout. beny by tooth extraction. Piroxicam is present throughout as a highly effective long-acting substance, so that it is possible to ensure effective. blood levels of piroxicam by oral administration once a day.

Some of the above conditions are chronic in nature and require long treatment. . In order to prevent undesirable side effects, it would be desirable to replace, after a certain period, topical administration by topical administration. Besides, it is. topical application suitable for milder cases or where there is even a small inflammatory plaque. >

It is an object of the present invention to provide a method of manufacture. an anti-inflammatory agent for topical administration. The composition should contain an effective amount of an anti-inflammatory agent, a non-toxic base, and a solvent.

Piroxicam · is very effective as an anti-inflammatory, but it is poorly water-soluble and not fat-soluble. When used to form a suspension while using conventional cream or ointment bases, it is absorbed very poorly by the skin and the expected therapeutic effect cannot be achieved. Moreover, as follows. the obtained composition is sticky and is unpleasant to apply to a larger area of skin. The active ingredient is

2410S2 also wipes clothing. It would seem possible to apply piroxicam in the form of an alcoholic solution, for example an ethanolic solution. However, even in this case, piroxicam precipitates on the skin when the solvent evaporates and the skin is not absorbed sufficiently.

The gel type composition can be obtained by adding a polymer to the mixture of lower alkanol and water. This is usually a convenient form of topical administration because it is refreshing and does not stick anywhere. However, this type of formulation cannot be obtained with piroxicam in the conventional manner, since piroxicam is only slightly soluble in water and any other solvent. In the presence of water, it is converted to a hydrate which is even less soluble than the free substance and, in addition, the hydrate gradually crystallizes. This crystallization not only further reduces the ability of piroxicam to be absorbed by the skin, but also changes the stability of the gel-type pharmaceutical composition.

Other problems arise if that lubrication gelovéhotypu ¹ is applied to the skin because the skin of sodium chloride · also causes crystallization of piroxicam. The resulting hydrate forms a yellowish layer on the skin and also wipes into · clothing or any other material.

Similar problems also arise when applying a gel-type composition to the sweaty skin, since the gel-forming polymer is also salted and, as a result, film formation occurs. The use of the composition is then subjectively unpleasant and again the active ingredient is lost and thus the therapeutic effect is poor.

It has now been found that it is possible to produce an anti-inflammatory composition for topical use with very good penetration because of the above disadvantages. Indeed, it has been shown that when an anti-inflammatory effective amount of piroxicam is mixed with a water-soluble base, a solvent, a gel-forming agent and, if necessary, an appropriate amount of a film-forming agent, an anti-inflammatory agent can be obtained. use with a high therapeutic effect and good stability, moreover, the composition is pleasant to use.

The composition of the present invention comprises lower C 2 -C 6 alkylene glycol, glycerol and polyethylene glycol having an average molecular weight of 200-2,000.

Thus, the anti-inflammatory agent produced by the method of the invention comprises piroxicam, a lower C 1 -C 4 alkanol, water, a gel forming carboxyvinyl polymer, one or more polyhydric alcohols from the lower C 2 -C 6 alkylene glycol group. glycerol and polyethylene glycol having an average molecular weight of 200 to 2,000 and one or more alkanolamines improving the solubility of piroxicam from the group consisting of monoalkanolamines of 1 to 4 carbon atoms, dialkanolamines of 2 to 8 carbon atoms and trialkanolamines of 3 to 12 carbon atoms, The pH of the composition is between 6.5 and 9.0.

The anti-inflammatory composition thus obtained may contain, in addition to the above ingredients, an effective amount of a carboxymethylcellulose, hydroxyethylcellulose or polyvinylpyrrolidone film-forming agent, again in the range of 6.5 to 9.0.

The composition produced by the process of the invention typically contains 0.3 to 2.0% by weight of piroxicam based on the total weight of the composition. If less is used, it is not possible to obtain satisfactory anti-inflammatory effects;

Examples of lower alcohols include methanol, ethanol, isopropanol and butanol. The preferred amount of lower alkanol is 10 to 50% by weight of the composition.

The preferred amount of water is 30 to 60% by weight.

The lower C 2 -C 6 alkylene glycol may be, for example, ethylene glycol, propylene glycol and butylene glycol. Instead of glycol, glycerol or polyethylene glycol with an average molecular weight of 200-2000 may also be used. Only one type of polyhydric alcohol or a mixture of these alcohols may be used. The preferred amount of this alcohol is in the range of 5 to 40 wt%. The use of an amount of polyhydric alcohol greater than 40% is not preferred because in this case the use of the composition is subjectively unpleasant. Although it is known that polyhydric alcohols can dissolve the active ingredients in the bases of a topical formulation, it is particularly surprising that polyhydric alcohols mixed with the above-mentioned alkanolamines can prevent the conversion of piroxicam to a hydrate and thereby prevent i. forming the above-mentioned yellow layer on the skin.

As can be seen from Table 1 below, if the composition does not contain polyhydric alcohols, piroxicam crystallizes on the skin as a yellow layer.

Table 1

Formation of yellow layer (piroxicam hydrate)

Means AND (B) C D polyhydric alcohol polyethylene glycol polyethylene glycol polyethylene glycol and propylene glycol 0 concentration in mass % 20 May 30 25 0 formation of a yellow layer No No No Yes

In the preparation of the composition according to the invention, agents are used which facilitate the solubility of piroxicam in the base. This agent is selected from the group of alkanolamines. Monoalkanolamines, dialkanolamines and trialkanolamines have been shown to be highly effective in increasing the solubility of piroxicam in the composition as well as increasing its skin permeability. These are monoalkanolamines having 1 to 4 carbon atoms, for example methanolamine, ethanolamine, propanolamine and butanolamine. The dialkanolamines may have 2 to 8 carbon atoms, for example dimethanolamine, diethanolamine, dipropanoaamine and dibuaanoaam, traaRa4o and o contain from 3 to 12 carbon atoms, e.g. ^ Λυ ^ ηοΐamine.

The solitizing ability of these alkanolamines would be! demonstrated in the mystery of the experiment in which the ability of these amines to dissolve piroxicam was compared with that of other solublizing agents. The results are given in English ^, Ubudce 2.

Table 2

Piroxicam solubility enhancers

Substance

Solvent ·: water solubility of piroxicam (mg / g)

Quantity {%)

ethanolamine 10 392 diethanolamine 10 204 di-isopropanolamine 10 195 di-isopropyl adipate 10 1,2 * diethylsebacate 10 2,0 * N-ethyl-o-crotonotoluidide 10 1,8 * isopropyl myristate 10 0,4 * ammonia 10 60.0 control 0 0.01 The solvent was a mixture water / ethanol 1: 1.

Only one type of alkanolamine or multiple types may be used at a time. The preferred amount of alkanolamines is up to 3% by weight. This amount is sufficient to dissolve piroxicam in the base, but otherwise the amount of alkanolamines is not limited.

Carboxyvinyl polymers are used to form a gel for the topical formulation of the present invention. They are hydrophilic polymers prepared by polymerizing monomers derived from acrylic acid. These polymers are commercially available [Goodrich Chemical USA, Carbopole 934 940 or 941 and Wako Pure Chemicals, Japan Hivisxako 103, 104 or 105j.

The carboxyvinyl polymer aqueous solution is acidic because the polymer contains free carboxyl groups. By neutralizing this aqueous solution with an appropriate base, it forms a gel with the desired viscosity. Bases which can be used are, for example, one of the abovementioned alkanolamines, inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and organic bases such as alkylamines, dialkylamines or trialkylamines.

The preferred amount of gel-forming agent is 0.2 to 2.0% by weight.

The gel type topical formulation containing the carboxyvinyl polymer is usually stable. It has a constant viscosity with very small changes due to temperature or time. As already mentioned, some problems arise when applying a composition comprising a carboxyvinyl polymer to the skin. Sometimes it is salted out by the action of sodium chloride in sweat, and then clusters are formed that easily disintegrate. In this case, the active ingredient is lost before being absorbed by the skin, and in addition the use of the composition is subjectively unpleasant.

The composition should therefore be applied to the cleansed skin. It has been shown that when certain hydrophilic polymers are incorporated into the composition, the composition can be applied topically to the sweaty skin to form a film.

Japanese Published Patent Application No. 55-40,604 discloses a similar phenomenon which is prevented by the use of hydroxypropylcellulose. Hydroxypropylcellulose, however, is an ineffective film-forming film 241062 has been shown in experiments, the results of which are shown in Table 3 below. Obviously, very good results were obtained.

using a composition according to the invention.

Polyvinylpyrrolidone, carboxymethylcellulose and hydroxyethylcellulose are more suitable for use herein. The ability of these substances is shown in Table 3

The film-forming ability of the composition containing piroxicam ¹

Film-forming agent application to normal skin application to skin with sodium chloride solution polyvinylpyrrolidone (1.0%) carboxymethylcellulose (1.0%) hydroxyethylcellulose (1.0%) hydroxyethylcellulose (0.5%) j Good film good film good film good film small amount of soft clusters good film good film good film good film large amount of soft clusters iThe composition used has the composition shown in the following table 4

Table 4

A formulation containing 1% piroxicam

Component Weight % piroxicam 1.0 carboxyvinyl polymer 940 1.0 ethanol 30.0 propylene glycol 20.0 ethylene glycol 10.0 diethanolamine 1.5 distilled water to 100 ALIGN!

Only one type of film-assisting agent or a plurality of such agents can be used. The preferred amount is 0.2 to 2.0% by weight based on the total weight of the composition.

The topical anti-inflammatory agent produced by the method of the invention has a pH of 6.5 to 9.0, preferably 6.5 to 8.0. It is generally believed that the absorption of the active ingredient through the skin depends on the ratio of fat solubility to water solubility such that a high ratio is preferred, but too high a ratio also reduces skin absorption and penetration. The pKa for piroxicam is 1.5-5.1. The preferred pH for the composition according to the invention is 6.5 to 8.0, since in this area the active ingredient is partly present in the form obtained and alkanolal amines can also be used within the same range. At a pH greater than 9.0, piroxicam is chemically unstable and may degrade or deteriorate.

Accordingly, the composition of the invention is prepared as follows:

(1) dispersing the carboxyvinyl polymer and optionally a film forming agent in distilled water;

3) independently dissolve piroxicam in aqueous alkanolamine until completely dissolved, optionally with the addition of a neutralizing agent; and

4) adding the mixture of step 3 to the mixture of step 2 and mixing the two mixtures into a gel-type composition.

The composition thus obtained is stable for a long period of storage and has very good anti-inflammatory properties, as will be apparent from the following examples.

Example 1

A gel-type composition for external use of pH 7.9 can be obtained by mixing the following components:

Component

Weight% piroxicam carboxyvinylpolymer 940 ethanol propylene glycol diethanolamine hydroxyethylcellulose polyvinylpyrrolidone K-30 distilled water

1.0

1.0

30.0

30.0

1.5

0.5

0,5 remaining share up to 100

Example 2

A gel-type composition for external use of pH 7.8 can be obtained by mixing the following components:

Piroxicam component

Weight%

1.0

2) the dispersion is mixed homogeneously with lower alkanols, glycols, glycerol or polyethylene glycol,

241062 9 10 carboxyvinylpolymer 940 1.0 Component Weight% ethanol 30.0 glycerine 20.0 piroxicam 1.0 polyethylene glycol 300 10.0 carboxyvinylpolymer 940 1.0 diisopropanolamine 1.7 ethanol 30.0 Distilled water remaining share glycerine 20.0 to 100 diethanolamine 1.3

triethylamine sufficient

Example 3 hydroxyethylcellulose 0.5 distilled science remaining share Means for external use of gel to 100 pH 8.0 can be obtained by mixing following components: Example 7 Component Weight% Means for external poi : living oxen- pH 7.6 can be obtained by mixing piroxicam 1.0 following components: carboxyvinylpolymer 940 1.0 ethanol 30.0 Component Weight% propylene glycol 10.0 glycerine 10.0 piroxicam 1.0 diisopropanolamine 1,8 carboxyvinylpolymer 940 0.7 hydroxyethylcellulose 1.0 ethanol 35.0 Distilled water remaining share propylene glycol 20.0 to 100 polyethylene glycol 300 10.0 diisopropanolamine 1.5 Example 4 Distilled water remaining share to 100 Means for external use of gel Example 8 6 pH 7.3 can be obtained by mixing following components: Means for external use of gel pH 6.7 can be obtained by mixing Component Weight% following components: piroxicam 1.0 Component Weight% carboxyvinylpolymer 940 1.0 ethanol 30.0 piroxicam 1.0 glycerine 30.0 carboxyvinylpolymer 940 1.0 diethanolamine 1.3 ethanol 40.0 Distilled water remaining share polyethylene glycol 300 20.0 to 100 diisopropanolamine 1.0 triethylamine sufficient Example 5 Distilled water remaining share do-100 Means for external use of gel pH 7.7 can be obtained by mixing Example 9 following components: Means for external use of gel- Component Weight ° / o pH 7.7 can be obtained by mixing following components: piroxicam 1.0 carboxyvinylpolymer 940 1.0 Component Weight% ethanol 30.0 propylene glycol 10.0 piroxicam 0.5 polyethylene glycol 300 10.0 carboxyvinylpolymer 940 0.7 diethanolamine 1.7 ethanol 25.0 carboxymethylcellulose 1.0 propylene glycol 20.0 Distilled water remaining share benzyl alcohol 1.0 to 100 hydroxyethylcellulose 0.4 diisopropanolamine 1,2 Example 6 water 51.2

An externally used gel-type formulation of pH 8.2 can be obtained by mixing the following components: An externally-used gel-type formulation at pH 7.8 can be obtained by mixing the following components:

Component Weight% piroxicam 1.0 carboxyvinylpolymer 940 0.9 ethanol 30.0 propylene glycol 7.5 polyethylene glycol 300 7.5 benzyl alcohol 1.0 hydroxyethylcellulose 0.5 diisopropanolamine 1.7 water 49.9

Example 11

Analgesic tests

The composition of Example 10 containing 1% piroxicam was examined at a dose of 100 milligrams per mouse by applying the composition locally to the hind paws to a group of 10 mice and then investigating the analgesic effect on the pain induced in the joints. The pain stimulus threshold was measured after 5 hours with an analgesimeter (UGO BASILE), the results are summarized in the following table.

Table 5

Test substance

Pain threshold (g) before administration hours after administration of the pi / o / o control

46.7 + 3.3

42.2 + 3.2

46.7 + 2.0

105.6 + 17.5

It is clear from the above results that the composition of the present invention has local analgesic activity.

Example 12

Anti-inflammatory effect &

The anti-inflammatory activity of the composition of the invention was determined using a standard rat paw swelling test caused by carrageenan. The method has been described in C. A. Winter et al., Proceedings of the Society for Experimental Biology and Medicine, Vol. 111, p. 544 [1962]. A composition with a concentration of 1% piroxicam, prepared according to Example 10, was administered topically at a dose of 100 mg per rat. The results obtained are shown in Table 6 below as inhibition of edema formation in% compared to untreated control animals and animals administered piroxicam orally at a dose of 1 mg / kg.

Table 6

Treatment of% inhibition of edema% piroxicam as a topical formulation41.6 oral administration39.6 control—

From the results, it is clear that the compositions made by the method of the invention prevent swelling as effectively as the oral compositions.

Claims (3)

I will invent the object A method for producing an anti-inflammatory composition for topical administration in the form of a gel comprising in an aqueous system an anti-inflammatory effective amount of pyroxicam, 10 to 50% by weight of a lower alcohol, carboxyvinyl polymer in an amount necessary to form a gel at least one alkanolamine in an amount permitting the solubility of piroxicam and optionally an effective amount of at least one film-forming agent and, in addition, water to < 100%, wherein the anti-inflammatory agent has a pH of 6.5 to 9.0, characterized in that (a) dispersing in water a hydrophilic acrylic acid-based carboxyvinyl polymer having an average molecular weight of 1 250 000 to 4 000 00, and optionally a film-forming agent selected from the group comprising carbioxymethylcellulose, hydroxymethylcellulose and polyvinylpyrrolidone in water, to form an aqueous dispersion; (b) mixing the resulting aqueous dispersion with a lower alcohol having from 1 to 4 carbon atoms and a polyhydric alcohol selected from the group consisting of lower alkylene glycol of 2 to 6 carbon atoms, glycerol and polyethylene glycol having an average molecular weight of 200 to 2000; (c) piroxicam is dissolved in an aqueous alkanolamine solution selected from the group consisting of monoalkanolamine of 1 to 4 carbon atoms, dialkanolamine of 2 to 8 carbon atoms and trialkanolamine of 3 to 12 carbon atoms; and d) mixing the aqueous solution of step c) and the resulting aqueous dispersion obtained in step b) and mixing the resulting mixture until gel formation. 2. The method of claim 1, wherein piroxicam is used in a concentration of 0.3 to 0.5 2.0% by weight based on the total weight of the composition. 3. A process according to claim 1 wherein the carboxyvinyl polymer is used in a concentration of 0.2 to 2.0% by weight based on the total weight of the composition.